Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19
Authors: Eleftherios Mylonakis, Christina Barkauskas, Garyfallia Poulakou, Barnaby E. Young
Journal: Annals of Internal Medicine (2023)

LettersFebruary 2023Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19FREEEleftherios Mylonakis, MD, PhD, Christina Barkauskas, MD, Garyfallia Poulakou, MD, PhD, Barnaby E. Young, MD, PhD, on behalf of the ACTIV-3/TICO Study Group*Eleftherios Mylonakis, MD, PhDWarren Alpert Medical School of Brown University, Providence, Rhode Island, Christina Barkauskas, MDDuke University Medical Center, Durham, North Carolina, Garyfallia Poulakou, MD, PhDNational and Kapodistrian University of Athens, Athens, Greece, Barnaby E. Young, MD, PhDNational Centre for Infectious Diseases, Singapore, on behalf of the ACTIV-3/TICO Study Group*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L22-0456 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE: We share Dr. Narasaraju and colleagues' belief about the need to improve the care of patients hospitalized with COVID-19. Their concerns about the design of the ACTIV-3/TICO trial of ensovibep can be summarized as follows: it failed to establish the efficacy of ensovibep, used 7-category ordinal outcomes as a primary outcome rather than a surrogate marker, and had limitations imposed by combining remdesivir with ensovibep.Concerning the first 2 points, as discussed in our article, the antiviral management of patients hospitalized with COVID-19 remains a major challenge after several large clinical trials. ACTIV-3/TICO is a multigroup, multistage platform master protocol that aims to rapidly evaluate the safety and efficacy of novel antiviral therapeutic candidates for adults hospitalized with COVID-19. Given these aims, the primary outcome for agents tested in this platform was chosen for its immediate clinical relevance: time to sustained recovery over 90 days of follow-up. In order to efficiently evaluate multiple investigational agents, futility was assessed after approximately 300 patients had completed the day 5 assessment visit. This assessment was based on supplemental oxygen requirements and organ dysfunction on day 5. These intermediate clinical outcomes were used to determine clinical progression and improvement and strongly correlate with sustained recovery through 90 days (1).When selected judiciously, surrogate laboratory markers could be useful indicators of clinical response; in addition, there are established criteria for surrogacy (2). To our knowledge, no work has established a surrogate for the clinical outcomes that are most meaningful for the target population (that is, patients hospitalized with COVID-19). Neither serum viral load nor the proposed markers studied in animals are sufficiently robust. For example, concerning serum viral load, in Jacobs and associates' study (3) viremia was detected in only 52.6% of patients not in the intensive care unit. Such serum and sputum markers of lung alveolar epithelial cell injury as podoplanin or circulating epithelial cell markers similarly are not clinically tested markers of antiviral efficacy. Along with other markers—such as serum nucleocapsid antigen, which was included in our study—these are important areas for further research (4).Regarding the last point, the goal is to improve standard of care in adults hospitalized with COVID-19. According to established treatment guidelines (5), standard of care among such patients could include remdesivir. Withholding the standard of care treatment would challenge equipoise and would not advance the research question addressed in the trial: whether ensovibep improves relevant clinical outcomes when added to standard of care treatment.References1. Lundgren JD, Grund B, Barkauskas CE, et al. ACTIV-3/TICO LY-CoV555 Study Group. A neutralizing monoclonal antibody for hospitalized patients with covid-19. N Engl J Med. 2021;384:905-14. [PMID: 33356051] doi:10.1056/NEJMoa2033130 CrossrefMedlineGoogle Scholar2. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431-40. [PMID: 2727467] CrossrefMedlineGoogle Scholar3. Jacobs JL, Bain W, Naqvi A, et al. Severe acute respiratory syndrome coronavirus 2 viremia is associated with coronavirus disease 2019 severity and predicts clinical outcomes. Clin Infect Dis. 2022;74:1525-33. [PMID: 34374761] doi:10.1093/cid/ciab686 CrossrefMedlineGoogle Scholar4. ACTIV-3/TICO Study Group. The association of baseline plasma SARS-CoV-2 nucleocapsid antigen level and outcomes in patients hospitalized with COVID-19. Ann Intern Med. 2022;175:1401-10. [PMID: 36037469] doi:10.7326/M22-0924 LinkGoogle Scholar5. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. 2022. Accessed at www.covid19treatmentguidelines.nih.gov on 12 September 2022. Google Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Eleftherios Mylonakis, MD, PhD; Christina Barkauskas, MD; Garyfallia Poulakou, MD, PhD; Barnaby E. Young, MD, PhDAffiliations: Warren Alpert Medical School of Brown University, Providence, Rhode IslandDuke University Medical Center, Durham, North CarolinaNational and Kapodistrian University of Athens, Athens, GreeceNational Centre for Infectious Diseases, Singapore* For members of the ACTIV-3/TICO Study Group, see Supplement 1 of the original article at www.acpjournals.org/doi/suppl/10.7326/M22-1503.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1503. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEfficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 Teluguakula Narasaraju , Amita Krishnappa , Marko Radic , and Vincent T.K. Chow Metrics February 2023Volume 176, Issue 2KeywordsCOVID-19Clinical trialsCritical careData and safety monitoring boardsHealth statisticsHospital medicineHospitalizationsInfectious diseasesSafetyVeteran care ePublished: 21 February 2023 Issue Published: February 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...